phagocyte

File:Professeur Metchnikoff, portrait du scientifique dans un laboratoire de recherche.jpg

The Russian zoologist Ilya Ilyich Mechnikov (1845–1916) first recognized that specialized cells were involved in defense against microbial infections.{{cite journal |vauthors=Kaufmann SH|title=Immunology's Coming of Age |journal=Frontiers in Immunology |volume=10 |page=684 |date=2019 |pmid=31001278 |pmc=6456699 |doi=10.3389/fimmu.2019.00684 |doi-access=free }} In 1882, he studied motile (freely moving) cells in the larvae of starfishes, believing they were important to the animals' immune defenses. To test his idea, he inserted small thorns from a tangerine tree into the larvae. After a few hours, he noticed that the motile cells had surrounded the thorns. Mechnikov traveled to Vienna and shared his ideas with Carl Friedrich Claus who suggested the name "phagocyte" (from the Greek words {{lang|grc-Latn|phagein}}, meaning "to eat or devour", and {{lang|grc-Latn|kutos}}, meaning "hollow vessel"{{cite book |title=The Shorter Oxford English Dictionary |vauthors=Little C, Fowler HW, Coulson J |publisher=Oxford University Press (Guild Publishing) |year=1983 |pages=1566–67}}) for the cells that Mechnikov had observed.{{cite journal |vauthors=Aterman K | title = Medals, memoirs—and Metchnikoff | journal = J. Leukoc. Biol. | volume = 63 | issue = 4 | pages = 515–17 | date = April 1, 1998 | pmid = 9544583 | doi = 10.1002/jlb.63.4.515 | s2cid = 44748502 | doi-access = free }}

A year later, Mechnikov studied a fresh water crustacean called Daphnia, a tiny transparent animal that can be examined directly under a microscope. He discovered that fungal spores that attacked the animal were destroyed by phagocytes. He went on to extend his observations to the white blood cells of mammals and discovered that the bacterium Bacillus anthracis could be engulfed and killed by phagocytes, a process that he called phagocytosis.{{cite web|url=http://nobelprize.org/nobel_prizes/medicine/laureates/1908/mechnikov-bio.html|title=Ilya Mechnikov|publisher=The Nobel Foundation|access-date=December 19, 2014}} Mechnikov proposed that phagocytes were a primary defense against invading organisms.

In 1903, Almroth Wright discovered that phagocytosis was reinforced by specific antibodies that he called opsonins, from the Greek opson, "a dressing or relish".{{Harvnb|Delves|Martin|Burton|Roit|2006|p=263}} Mechnikov was awarded (jointly with Paul Ehrlich) the 1908 Nobel Prize in Physiology or Medicine for his work on phagocytes and phagocytosis.

Although the importance of these discoveries slowly gained acceptance during the early twentieth century, the intricate relationships between phagocytes and all the other components of the immune system were not known until the 1980s.{{Harvnb|Robinson|Babcock|1998|p=vii}}

{{main|Phagocytosis}}

File:Phagocytosis in three steps.png

Phagocytosis is the process of taking in particles such as bacteria, invasive fungi, parasites, dead host cells, and cellular and foreign debris by a cell.{{Harvnb|Ernst|Stendahl|2006|p=4}} It involves a chain of molecular processes.{{Harvnb|Ernst|Stendahl|2006|p=78}}{{cite journal |vauthors=Feldman MB, Vyas JM, Mansour MK |title=It takes a village: Phagocytes play a central role in fungal immunity |journal=Seminars in Cell & Developmental Biology |volume=89 |issue= |pages=16–23 |date=May 2019 |pmid=29727727 |pmc=6235731 |doi=10.1016/j.semcdb.2018.04.008}} Phagocytosis occurs after the foreign body, a bacterial cell, for example, has bound to molecules called "receptors" that are on the surface of the phagocyte. The phagocyte then stretches itself around the bacterium and engulfs it. Phagocytosis of bacteria by human neutrophils takes on average nine minutes.{{cite journal |vauthors=Hampton MB, Vissers MC, Winterbourn CC | title = A single assay for measuring the rates of phagocytosis and bacterial killing by neutrophils | journal = J. Leukoc. Biol. | volume = 55 | issue = 2 | pages = 147–52 | date = February 1994 | pmid = 8301210 | doi = 10.1002/jlb.55.2.147| url = http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=8301210 | archive-url = https://archive.today/20121228084302/http://www.jleukbio.org/cgi/pmidlookup?view=long&pmid=8301210 | archive-date = December 28, 2012 | s2cid = 44911791 | access-date = December 19, 2014 }} Once inside this phagocyte, the bacterium is trapped in a compartment called a phagosome. Within one minute the phagosome merges with either a lysosome or a granule to form a phagolysosome. The bacterium is then subjected to an overwhelming array of killing mechanisms{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=6–7}} and is dead a few minutes later. Dendritic cells and macrophages are not so fast, and phagocytosis can take many hours in these cells. Macrophages are slow and untidy eaters; they engulf huge quantities of material and frequently release some undigested back into the tissues. This debris serves as a signal to recruit more phagocytes from the blood.{{Harvnb|Sompayrac|2019|p=2}} Phagocytes have voracious appetites; scientists have even fed macrophages with iron filings and then used a small magnet to separate them from other cells.{{Harvnb|Sompayrac|2019|p=2}}

File:Opsonin.png

A phagocyte has many types of receptors on its surface that are used to bind material. They include opsonin receptors, scavenger receptors, and Toll-like receptors. Opsonin receptors increase the phagocytosis of bacteria that have been coated with immunoglobulin G (IgG) antibodies or with complement. "Complement" is the name given to a complex series of protein molecules found in the blood that destroy cells or mark them for destruction.{{Harvnb|Sompayrac|2019|pp=13–16}} Scavenger receptors bind to a large range of molecules on the surface of bacterial cells, and Toll-like receptors—so called because of their similarity to well-studied receptors in fruit flies that are encoded by the Toll gene—bind to more specific molecules including foreign DNA and RNA.{{cite journal |vauthors=Freund I, Eigenbrod T, Helm M, Dalpke AH |title=RNA Modifications Modulate Activation of Innate Toll-Like Receptors |journal=Genes |volume=10 |issue=2 |date=January 2019 |page=92 |pmid=30699960 |pmc=6410116 |doi=10.3390/genes10020092|doi-access=free }} Binding to Toll-like receptors increases phagocytosis and causes the phagocyte to release a group of hormones that cause inflammation.

File:Phagocytosis2.png

The killing of microbes is a critical function of phagocytes that is performed either within the phagocyte (intracellular killing) or outside of the phagocyte (extracellular killing).{{cite journal

|vauthors=Dale DC, Boxer L, Liles WC

| title = The phagocytes: neutrophils and monocytes

| journal = Blood | volume = 112 | issue = 4 | pages = 935–45 |date=August 2008 | pmid = 18684880 | doi = 10.1182/blood-2007-12-077917

| s2cid = 746699

| doi-access = free }}

When a phagocyte ingests bacteria (or any material), its oxygen consumption increases. The increase in oxygen consumption, called a respiratory burst, produces reactive oxygen-containing molecules that are anti-microbial.{{cite journal|title=Respiratory burst in human neutrophils|journal=Journal of Immunological Methods|date=December 17, 1999|first=C|last=Dahlgren|author2=A Karlsson|volume=232|issue=1–2|pages=3–14|pmid=10618505|doi=10.1016/S0022-1759(99)00146-5}} The oxygen compounds are toxic to both the invader and the cell itself, so they are kept in compartments inside the cell. This method of killing invading microbes by using the reactive oxygen-containing molecules is referred to as oxygen-dependent intracellular killing, of which there are two types.

The first type is the oxygen-dependent production of a superoxide, which is an oxygen-rich bacteria-killing substance.{{cite journal|title=NADPH oxidase|journal=The International Journal of Biochemistry & Cell Biology|year=1996|first=KP|last=Shatwell|author2=AW Segal|volume=28|issue=11|pages=1191–95|pmid=9022278|doi=10.1016/S1357-2725(96)00084-2}} The superoxide is converted to hydrogen peroxide and singlet oxygen by an enzyme called superoxide dismutase. Superoxides also react with the hydrogen peroxide to produce hydroxyl radicals, which assist in killing the invading microbe.

The second type involves the use of the enzyme myeloperoxidase from neutrophil granules.{{cite journal |vauthors=Klebanoff SJ | title = Myeloperoxidase | journal = Proc. Assoc. Am. Physicians | volume = 111 | issue = 5 | pages = 383–89 | year = 1999 | pmid = 10519157 | doi = 10.1111/paa.1999.111.5.383}} When granules fuse with a phagosome, myeloperoxidase is released into the phagolysosome, and this enzyme uses hydrogen peroxide and chlorine to create hypochlorite, a substance used in domestic bleach. Hypochlorite is extremely toxic to bacteria. Myeloperoxidase contains a heme pigment, which accounts for the green color of secretions rich in neutrophils, such as pus and infected sputum.{{cite journal |vauthors=Meyer KC | title = Neutrophils, myeloperoxidase, and bronchiectasis in cystic fibrosis: green is not good | journal = J. Lab. Clin. Med. | volume = 144 | issue = 3 | pages = 124–26 |date=September 2004 | pmid = 15478278 | doi = 10.1016/j.lab.2004.05.014}}

File:Gram-stain of gonorrhoea.jpged pus showing Neisseria gonorrhoeae bacteria inside phagocytes and their relative sizes|alt=Pus under a microscope, there are many white blood cells with lobed nuclei. Inside some of the cells there are hundreds of bacteria that have been engulfed.]]

Phagocytes can also kill microbes by oxygen-independent methods, but these are not as effective as the oxygen-dependent ones. There are four main types. The first uses electrically charged proteins that damage the bacterium's membrane. The second type uses lysozymes; these enzymes break down the bacterial cell wall. The third type uses lactoferrins, which are present in neutrophil granules and remove essential iron from bacteria.{{Harvnb|Hoffbrand|Pettit|Moss|2005|p=118}} The fourth type uses proteases and hydrolytic enzymes; these enzymes are used to digest the proteins of destroyed bacteria.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=6–10}}

Interferon-gamma—which was once called macrophage activating factor—stimulates macrophages to produce nitric oxide. The source of interferon-gamma can be CD4⁺ T cells, CD8⁺ T cells, natural killer cells, B cells, natural killer T cells, monocytes, other macrophages, or dendritic cells.{{cite journal |vauthors=Schroder K, Hertzog PJ, Ravasi T, Hume DA | title = Interferon-gamma: an overview of signals, mechanisms and functions | journal = J. Leukoc. Biol. | volume = 75 | issue = 2 | pages = 163–89 | date = February 2004 | pmid = 14525967 | doi = 10.1189/jlb.0603252 | s2cid = 15862242 | doi-access = }} Nitric oxide is then released from the macrophage and, because of its toxicity, kills microbes near the macrophage. Activated macrophages produce and secrete tumor necrosis factor. This cytokine—a class of signaling molecule{{Harvnb|Delves|Martin|Burton|Roit|2006|p=188}}—kills cancer cells and cells infected by viruses, and helps to activate the other cells of the immune system.{{Harvnb|Sompayrac|2019|p=136}}

In some diseases, e.g., the rare chronic granulomatous disease, the efficiency of phagocytes is impaired, and recurrent bacterial infections are a problem.{{cite journal

|vauthors=Lipu HN, Ahmed TA, Ali S, Ahmed D, Waqar MA| title = Chronic granulomatous disease| journal = J Pak Med Assoc| volume = 58| issue = 9| pages = 516–18|date=September 2008| pmid = 18846805}} In this disease there is an abnormality affecting different elements of oxygen-dependent killing. Other rare congenital abnormalities, such as Chédiak–Higashi syndrome, are also associated with defective killing of ingested microbes.{{cite journal |vauthors=Kaplan J, De Domenico I, Ward DM | title = Chediak-Higashi syndrome | journal = Curr. Opin. Hematol. | volume = 15 | issue = 1 | pages = 22–29 |date=January 2008 | pmid = 18043242 | doi = 10.1097/MOH.0b013e3282f2bcce | s2cid = 43243529 }}

Viruses can reproduce only inside cells, and they can gain entry by using many of the receptors involved in immunity. Once inside the cell, viruses use the cell's biological machinery to their own advantage, forcing the cell to make hundreds of identical copies of themselves. Although phagocytes and other components of the innate immune system can, to a limited extent, control viruses, once a virus is inside a cell the adaptive immune responses, particularly the lymphocytes, are more important for defense.{{Harvnb|Sompayrac|2019|p=7}} At the sites of viral infections, lymphocytes often vastly outnumber all the other cells of the immune system; this is common in viral meningitis.{{cite journal |vauthors=de Almeida SM, Nogueira MB, Raboni SM, Vidal LR | title = Laboratorial diagnosis of lymphocytic meningitis | journal = Braz J Infect Dis | volume = 11 | issue = 5 | pages = 489–95 |date=October 2007 | pmid = 17962876 | doi = 10.1590/s1413-86702007000500010 | doi-access = free }} Virus-infected cells that have been killed by lymphocytes are cleared from the body by phagocytes.{{Harvnb|Sompayrac|2019|p=22}}

{{main|Apoptosis}}

In an animal, cells are constantly dying. A balance between cell division and cell death keeps the number of cells relatively constant in adults.{{cite journal |vauthors=Thompson CB| title=Apoptosis in the pathogenesis and treatment of disease| journal=Science| year=1995| volume=267| issue=5203| pages=1456–62| doi=10.1126/science.7878464| pmid=7878464 | bibcode=1995Sci...267.1456T| s2cid=12991980}} There are two different ways a cell can die: by necrosis or by apoptosis. In contrast to necrosis, which often results from disease or trauma, apoptosis—or programmed cell death—is a normal healthy function of cells. The body has to rid itself of millions of dead or dying cells every day, and phagocytes play a crucial role in this process.{{Harvnb|Sompayrac|2019|p=68}}

Dying cells that undergo the final stages of apoptosis{{cite web|url=http://www.merriam-webster.com/dictionary/apoptosis |title=Apoptosis |work=Merriam-Webster Online Dictionary |access-date=December 19, 2014 }} display molecules, such as phosphatidylserine, on their cell surface to attract phagocytes.{{cite journal

|vauthors=Li MO, Sarkisian MR, Mehal WZ, Rakic P, Flavell RA

| title = Phosphatidylserine receptor is required for clearance of apoptotic cells

| journal = Science | volume = 302 | issue = 5650 | pages = 1560–63 |date=November 2003 | pmid = 14645847 | doi = 10.1126/science.1087621

| s2cid = 36252352

}} (Free registration required for online access) Phosphatidylserine is normally found on the cytosolic surface of the plasma membrane, but is redistributed during apoptosis to the extracellular surface by a protein known as scramblase.{{cite journal |vauthors=Nagata S, Sakuragi T, Segawa K |title=Flippase and scramblase for phosphatidylserine exposure |journal=Current Opinion in Immunology |volume=62 |pages=31–38 |date=December 2019 |pmid=31837595 |doi=10.1016/j.coi.2019.11.009 |doi-access=free }}{{cite journal| vauthors=Wang X| title=Cell corpse engulfment mediated by C. elegans phosphatidylserine receptor through CED-5 and CED-12| journal=Science| year=2003| volume=302| issue=5650| pages=1563–1566| doi=10.1126/science.1087641| pmid=14645848| bibcode=2003Sci...302.1563W| s2cid=25672278| url=http://ntur.lib.ntu.edu.tw//handle/246246/161415| archive-url=https://web.archive.org/web/20210414033822/http://ntur.lib.ntu.edu.tw/handle/246246/161415| url-status=dead| archive-date=April 14, 2021}} (Free registration required for online access) These molecules mark the cell for phagocytosis by cells that possess the appropriate receptors, such as macrophages.{{cite journal|vauthors=Savill J, Gregory C, Haslett C | title=Eat me or die| journal=Science| year=2003| volume=302| issue=5650| pages=1516–17| doi=10.1126/science.1092533| pmid=14645835| hdl=1842/448| s2cid=13402617| hdl-access=free}} The removal of dying cells by phagocytes occurs in an orderly manner without eliciting an inflammatory response and is an important function of phagocytes.{{cite journal

|vauthors=Zhou Z, Yu X

| title = Phagosome maturation during the removal of apoptotic cells: receptors lead the way

| journal = Trends Cell Biol. | volume = 18 | issue = 10 | pages = 474–85 |date=October 2008 | pmid = 18774293 | doi = 10.1016/j.tcb.2008.08.002

| pmc = 3125982

}}

Phagocytes are usually not bound to any particular organ but move through the body interacting with the other phagocytic and non-phagocytic cells of the immune system. They can communicate with other cells by producing chemicals called cytokines, which recruit other phagocytes to the site of infections or stimulate dormant lymphocytes.{{Harvnb|Sompayrac|2019|p=3}} Phagocytes form part of the innate immune system, which animals, including humans, are born with. Innate immunity is very effective but non-specific in that it does not discriminate between different sorts of invaders. On the other hand, the adaptive immune system of jawed vertebrates—the basis of acquired immunity—is highly specialized and can protect against almost any type of invader.{{Harvnb|Sompayrac|2019|p=4}} The adaptive immune system is not dependent on phagocytes but lymphocytes, which produce protective proteins called antibodies, which tag invaders for destruction and prevent viruses from infecting cells.{{Harvnb|Sompayrac|2019|pp=27–35}} Phagocytes, in particular dendritic cells and macrophages, stimulate lymphocytes to produce antibodies by an important process called antigen presentation.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=171–184}}

{{main|Antigen presentation}}

File:MHC Class I processing.svg

Antigen presentation is a process in which some phagocytes move parts of engulfed materials back to the surface of their cells and "present" them to other cells of the immune system.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=456}} There are two "professional" antigen-presenting cells: macrophages and dendritic cells.{{cite web|url=http://pim.medicine.dal.ca/apc.htm|archive-url=https://web.archive.org/web/20080112211805/http://pim.medicine.dal.ca/apc.htm|archive-date=January 12, 2008|title=Antigen Presenting Cells (APC)|website=Dalhousie University|vauthors=Lee T, McGibbon A|year=2004|access-date=December 19, 2014}} After engulfment, foreign proteins (the antigens) are broken down into peptides inside dendritic cells and macrophages. These peptides are then bound to the cell's major histocompatibility complex (MHC) glycoproteins, which carry the peptides back to the phagocyte's surface where they can be "presented" to lymphocytes. Mature macrophages do not travel far from the site of infection, but dendritic cells can reach the body's lymph nodes, where there are millions of lymphocytes.{{Harvnb|Delves|Martin|Burton|Roit|2006|p=161}} This enhances immunity because the lymphocytes respond to the antigens presented by the dendritic cells just as they would at the site of the original infection.{{Harvnb|Sompayrac|2019|p=8}} But dendritic cells can also destroy or pacify lymphocytes if they recognize components of the host body; this is necessary to prevent autoimmune reactions. This process is called tolerance.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=237–242}}

{{main|Immunological tolerance}}

Dendritic cells also promote immunological tolerance,{{cite journal |vauthors=Lange C, Dürr M, Doster H, Melms A, Bischof F | title = Dendritic cell-regulatory T-cell interactions control self-directed immunity | journal = Immunol. Cell Biol. | volume = 85 | issue = 8 | pages = 575–81 | year = 2007 | pmid = 17592494 | doi = 10.1038/sj.icb.7100088 | s2cid = 36342899 }} which stops the body from attacking itself. The first type of tolerance is central tolerance, that occurs in the thymus. T cells that bind (via their T cell receptor) to self antigen (presented by dendritic cells on MHC molecules) too strongly are induced to die. The second type of immunological tolerance is peripheral tolerance.

Some self reactive T cells escape the thymus for a number of reasons, mainly due to the lack of expression of some self antigens in the thymus. Another type of T cell; T regulatory cells can down regulate self reactive T cells in the periphery.{{cite web|url=http://www.rockefeller.edu/labheads/steinman/dendritic_intro/immuneTolerance.php|title=Dendritic Cells and Immune Tolerance|last=Steinman|first=Ralph M.|year=2004|publisher=The Rockefeller University|access-date=December 19, 2014|archive-url=https://web.archive.org/web/20090311032056/http://www.rockefeller.edu/labheads/steinman/dendritic_intro/immuneTolerance.php|archive-date=March 11, 2009}} When immunological tolerance fails, autoimmune diseases can follow.{{cite journal|title=Immunological tolerance and autoimmunity|journal=Internal and Emergency Medicine|year=2006|first=S|last=Romagnani|volume=1|issue=3|pages=187–96|pmid=17120464|doi=10.1007/BF02934736|s2cid=27585046}}

File:Myeloid cells.png

Phagocytes of humans and other jawed vertebrates are divided into "professional" and "non-professional" groups based on the efficiency with which they participate in phagocytosis. The professional phagocytes are myeloid cells, which includes monocytes, macrophages, neutrophils, tissue dendritic cells and mast cells. One litre of human blood contains about six billion phagocytes.

All phagocytes, and especially macrophages, exist in degrees of readiness. Macrophages are usually relatively dormant in the tissues and proliferate slowly. In this semi-resting state, they clear away dead host cells and other non-infectious debris and rarely take part in antigen presentation. But, during an infection, they receive chemical signals—usually interferon gamma—which increases their production of MHC II molecules and which prepares them for presenting antigens. In this state, macrophages are good antigen presenters and killers. If they receive a signal directly from an invader, they become "hyperactivated", stop proliferating, and concentrate on killing. Their size and rate of phagocytosis increases—some become large enough to engulf invading protozoa.{{Harvnb|Sompayrac|2019|pp=16–17}}

In the blood, neutrophils are inactive but are swept along at high speed. When they receive signals from macrophages at the sites of inflammation, they slow down and leave the blood. In the tissues, they are activated by cytokines and arrive at the battle scene ready to kill.{{Harvnb|Sompayrac|2019|pp=18–19}}

File:NeutrophilerAktion.svg

When an infection occurs, a chemical "SOS" signal is given off to attract phagocytes to the site.{{Harvnb|Delves|Martin|Burton|Roit|2006|p=6}} These chemical signals may include proteins from invading bacteria, clotting system peptides, complement products, and cytokines that have been given off by macrophages located in the tissue near the infection site. Another group of chemical attractants are cytokines that recruit neutrophils and monocytes from the blood.Janeway, Chapter: [https://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=migration&rid=imm.section.203#206 Induced innate responses to infection.]

To reach the site of infection, phagocytes leave the bloodstream and enter the affected tissues. Signals from the infection cause the endothelial cells that line the blood vessels to make a protein called selectin, which neutrophils stick to on passing by. Other signals called vasodilators loosen the junctions connecting endothelial cells, allowing the phagocytes to pass through the wall. Chemotaxis is the process by which phagocytes follow the cytokine "scent" to the infected spot. Neutrophils travel across epithelial cell-lined organs to sites of infection, and although this is an important component of fighting infection, the migration itself can result in disease-like symptoms.{{cite journal |vauthors=Zen K, Parkos CA | title = Leukocyte-epithelial interactions | journal = Curr. Opin. Cell Biol. | volume = 15 | issue = 5 | pages = 557–64 |date=October 2003 | pmid = 14519390 | doi = 10.1016/S0955-0674(03)00103-0}} During an infection, millions of neutrophils are recruited from the blood, but they die after a few days.{{Harvnb|Sompayrac|2019|p=18}}

{{main|Monocytes}}

File:Monocytes, a type of white blood cell (Giemsa stained).jpg)]]

Monocytes develop in the bone marrow and reach maturity in the blood. Mature monocytes have large, smooth, lobed nuclei and abundant cytoplasm that contains granules. Monocytes ingest foreign or dangerous substances and present antigens to other cells of the immune system. Monocytes form two groups: a circulating group and a marginal group that remain in other tissues (approximately 70% are in the marginal group). Most monocytes leave the blood stream after 20–40 hours to travel to tissues and organs and in doing so transform into macrophages{{Harvnb|Hoffbrand|Pettit|Moss|2005|p=117}} or dendritic cells depending on the signals they receive.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=1–6}} There are about 500 million monocytes in one litre of human blood.

File:Gram stain of a macrophage with ingested S epidermidis bacteria.jpg of a macrophage with ingested S. epidermidis bacteria, seen as purple granules within its cytoplasm.]]

{{main|Macrophages}}

Mature macrophages do not travel far but stand guard over those areas of the body that are exposed to the outside world. There they act as garbage collectors, antigen presenting cells, or ferocious killers, depending on the signals they receive.{{Harvnb|Sompayrac|2019|p=136}} They derive from monocytes, granulocyte stem cells, or the cell division of pre-existing macrophages.{{cite journal

|vauthors=Takahashi K, Naito M, Takeya M

| title = Development and heterogeneity of macrophages and their related cells through their differentiation pathways

| journal = Pathol. Int. | volume = 46 | issue = 7 | pages = 473–85 |date=July 1996 | pmid = 8870002 | doi = 10.1111/j.1440-1827.1996.tb03641.x

| s2cid = 6049656

}} Human macrophages are about 21 micrometers in diameter.{{cite journal |vauthors=Krombach F, Münzing S, Allmeling AM, Gerlach JT, Behr J, Dörger M |title=Cell size of alveolar macrophages: an interspecies comparison |journal=Environ. Health Perspect. |volume=105 |pages=1261–63 |date=September 1997 |pmid=9400735 |pmc=1470168 |doi= 10.2307/3433544 |jstor=3433544 |issue=Suppl 5}}

File:Cutaneous abscess MRSA staphylococcus aureus 7826 lores.jpg oozing from an abscess caused by bacteria—pus contains millions of phagocytes|alt=A person's thigh with a red area that is inflamed. At the centre of the inflammation is a wound with pus.]]

This type of phagocyte does not have granules but contains many lysosomes. Macrophages are found throughout the body in almost all tissues and organs (e.g., microglial cells in the brain and alveolar macrophages in the lungs), where they silently lie in wait. A macrophage's location can determine its size and appearance. Macrophages cause inflammation through the production of interleukin-1, interleukin-6, and TNF-alpha.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=31–36}} Macrophages are usually only found in tissue and are rarely seen in blood circulation. The life-span of tissue macrophages has been estimated to range from four to fifteen days.{{Harvnb|Ernst|Stendahl|2006|p=8}}

Macrophages can be activated to perform functions that a resting monocyte cannot. T helper cells (also known as effector T cells or T_h cells), a sub-group of lymphocytes, are responsible for the activation of macrophages. T_h1 cells activate macrophages by signaling with IFN-gamma and displaying the protein CD40 ligand.{{Harvnb|Delves|Martin|Burton|Roit|2006|p=156}} Other signals include TNF-alpha and lipopolysaccharides from bacteria. T_h1 cells can recruit other phagocytes to the site of the infection in several ways. They secrete cytokines that act on the bone marrow to stimulate the production of monocytes and neutrophils, and they secrete some of the cytokines that are responsible for the migration of monocytes and neutrophils out of the bloodstream.{{Harvnb|Delves|Martin|Burton|Roit|2006|p=187}} T_h1 cells come from the differentiation of CD4⁺ T cells once they have responded to antigen in the secondary lymphoid tissues. Activated macrophages play a potent role in tumor destruction by producing TNF-alpha, IFN-gamma, nitric oxide, reactive oxygen compounds, cationic proteins, and hydrolytic enzymes.

{{main|Neutrophils}}

File:Neutrophils.jpg, the intra-cellular granules are visible in the cytoplasm (Giemsa stained) |alt=A round cell with a lobed nucleus surrounded by many slightly smaller red blood cells.]]

Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, constituting 50% to 60% of the total circulating white blood cells.{{cite book | last = Stvrtinová | first = Viera | author2 = Ján Jakubovský and Ivan Hulín | title = Inflammation and Fever from Pathophysiology: Principles of Disease | publisher = Academic Electronic Press | year = 1995 | location = Computing Centre, Slovak Academy of Sciences | chapter-url = http://nic.sav.sk/logos/books/scientific/node15.html | isbn = 978-80-967366-1-4 | chapter = Neutrophils, central cells in acute inflammation | access-date = December 19, 2014 | archive-url = https://web.archive.org/web/20101231014453/http://nic.sav.sk/logos/books/scientific/node15.html | archive-date = December 31, 2010 }} One litre of human blood contains about five billion neutrophils, which are about 10 micrometers in diameter{{Harvnb|Delves|Martin|Burton|Roit|2006|p=4}} and live for only about five days. Once they have received the appropriate signals, it takes them about thirty minutes to leave the blood and reach the site of an infection.{{Harvnb|Sompayrac|2019|p=18}} They are ferocious eaters and rapidly engulf invaders coated with antibodies and complement, and damaged cells or cellular debris. Neutrophils do not return to the blood; they turn into pus cells and die. Mature neutrophils are smaller than monocytes and have a segmented nucleus with several sections; each section is connected by chromatin filaments—neutrophils can have 2–5 segments. Neutrophils do not normally exit the bone marrow until maturity but during an infection neutrophil precursors called metamyelocytes, myelocytes and promyelocytes are released.{{cite journal |vauthors=Linderkamp O, Ruef P, Brenner B, Gulbins E, Lang F | title = Passive deformability of mature, immature, and active neutrophils in healthy and septicemic neonates | journal = Pediatr. Res. | volume = 44 | issue = 6 | pages = 946–50 |date=December 1998 | pmid = 9853933 | doi = 10.1203/00006450-199812000-00021 | doi-access = free }}

The intra-cellular granules of the human neutrophil have long been recognized for their protein-destroying and bactericidal properties.{{Harvnb|Paoletti|Notario|Ricevuti|1997|p=62}} Neutrophils can secrete products that stimulate monocytes and macrophages. Neutrophil secretions increase phagocytosis and the formation of reactive oxygen compounds involved in intracellular killing.{{cite journal |vauthors=Soehnlein O, Kenne E, Rotzius P, Eriksson EE, Lindbom L | title = Neutrophil secretion products regulate anti-bacterial activity in monocytes and macrophages | journal = Clin. Exp. Immunol. | volume = 151 | issue = 1 | pages = 139–45 |date=January 2008 | pmid = 17991288 | pmc = 2276935 | doi = 10.1111/j.1365-2249.2007.03532.x}} Secretions from the primary granules of neutrophils stimulate the phagocytosis of IgG-antibody-coated bacteria.{{cite journal |vauthors=Soehnlein O, Kai-Larsen Y, Frithiof R | title = Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages | journal = J. Clin. Invest. | volume = 118 | issue = 10 | pages = 3491–502 |date=October 2008 | pmid = 18787642 | pmc = 2532980 | doi = 10.1172/JCI35740 }} When encountering bacteria, fungi or activated platelets they produce web-like chromatin structures known as neutrophil extracellular traps (NETs). Composed mainly of DNA, NETs cause death by a process called netosis – after the pathogens are trapped in NETs they are killed by oxidative and non-oxidative mechanisms.{{cite journal |vauthors=Papayannopoulos V |title=Neutrophil extracellular traps in immunity and disease |journal=Nature Reviews. Immunology |volume=18 |issue=2 |pages=134–147 |date=February 2018 |pmid=28990587 |doi=10.1038/nri.2017.105|s2cid=25067858 }}

{{main|Dendritic cell}}

File:Dendritic cell.JPG

Dendritic cells are specialized antigen-presenting cells that have long outgrowths called dendrites,{{cite journal|vauthors=Steinman RM, Cohn ZA|title=Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution|journal=J. Exp. Med.|volume=137|issue=5|pages=1142–62|year=1973|pmid=4573839|doi=10.1084/jem.137.5.1142|pmc=2139237}} that help to engulf microbes and other invaders.{{cite web|url=http://www.rockefeller.edu/labheads/steinman/steinman-lab.php|title=Dendritic Cells|last=Steinman|first=Ralph|publisher=The Rockefeller University|access-date=December 19, 2014|archive-date=June 27, 2009|archive-url=https://web.archive.org/web/20090627151040/http://www.rockefeller.edu/labheads/steinman/steinman-lab.php|url-status=dead}}{{cite journal |vauthors=Guermonprez P, Valladeau J, Zitvogel L, Théry C, Amigorena S | title = Antigen presentation and T cell stimulation by dendritic cells | journal = Annu. Rev. Immunol. | volume = 20 | pages = 621–67 | year = 2002 | pmid = 11861614 | doi = 10.1146/annurev.immunol.20.100301.064828}} Dendritic cells are present in the tissues that are in contact with the external environment, mainly the skin, the inner lining of the nose, the lungs, the stomach, and the intestines.{{Harvnb|Hoffbrand|Pettit|Moss|2005|p=134}} Once activated, they mature and migrate to the lymphoid tissues where they interact with T cells and B cells to initiate and orchestrate the adaptive immune response.{{cite journal|vauthors=Sallusto F, Lanzavecchia A|title=The instructive role of dendritic cells on T-cell responses|journal=Arthritis Res.|volume=4|pages=S127–32|year=2002|pmid=12110131|doi=10.1186/ar567|pmc=3240143|issue=Suppl 3 |doi-access=free }}

Mature dendritic cells activate T helper cells and cytotoxic T cells.{{Harvnb|Sompayrac|2019|pp=45–46}} The activated helper T cells interact with macrophages and B cells to activate them in turn. In addition, dendritic cells can influence the type of immune response produced; when they travel to the lymphoid areas where T cells are held they can activate T cells, which then differentiate into cytotoxic T cells or helper T cells.

{{main|Mast cell}}

Mast cells have Toll-like receptors and interact with dendritic cells, B cells, and T cells to help mediate adaptive immune functions.{{cite journal |vauthors=Novak N, Bieber T, Peng WM |title=The immunoglobulin E-Toll-like receptor network |journal=International Archives of Allergy and Immunology |volume=151 |issue=1 |pages=1–7 |year=2010 |pmid=19672091 |doi=10.1159/000232565 |url=https://www.karger.com/Article/PDF/000232565 |access-date=December 19, 2014 |doi-access=free }} Mast cells express MHC class II molecules and can participate in antigen presentation; however, the mast cell's role in antigen presentation is not very well understood.{{cite journal |vauthors=Kalesnikoff J, Galli SJ |title=New developments in mast cell biology |journal=Nature Immunology |volume=9 |issue=11 |pages=1215–23 |date=November 2008 |pmid=18936782 |pmc=2856637 |doi=10.1038/ni.f.216}} Mast cells can consume and kill gram-negative bacteria (e.g., salmonella), and process their antigens.{{cite journal |vauthors=Malaviya R, Abraham SN | title = Mast cell modulation of immune responses to bacteria | journal = Immunol. Rev. | volume = 179 | pages = 16–24 |date=February 2001 | pmid = 11292019 | doi = 10.1034/j.1600-065X.2001.790102.x | s2cid = 23115222 }} They specialize in processing the fimbrial proteins on the surface of bacteria, which are involved in adhesion to tissues.{{cite journal |vauthors=Connell I, Agace W, Klemm P, Schembri M, Mărild S, Svanborg C |title=Type 1 fimbrial expression enhances Escherichia coli virulence for the urinary tract |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=18 |pages=9827–32 |date=September 1996 |pmid=8790416 |pmc=38514 |doi= 10.1073/pnas.93.18.9827 |bibcode=1996PNAS...93.9827C |doi-access=free }}{{cite journal |vauthors=Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JD | title = Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells | journal = J. Immunol. | volume = 156 | issue = 4 | pages = 1490–96 |date=February 1996 | pmid = 8568252 | url = http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=8568252 | doi = 10.4049/jimmunol.156.4.1490 | s2cid = 7917861 | access-date = December 19, 2014 }} In addition to these functions, mast cells produce cytokines that induce an inflammatory response.{{cite journal |vauthors=Taylor ML, Metcalfe DD | title = Mast cells in allergy and host defense | journal = Allergy Asthma Proc | volume = 22 | issue = 3 | pages = 115–19 | year = 2001 | pmid = 11424870 | doi = 10.2500/108854101778148764}} This is a vital part of the destruction of microbes because the cytokines attract more phagocytes to the site of infection.{{cite journal |vauthors=Urb M, Sheppard DC |title=The role of mast cells in the defence against pathogens |journal=PLOS Pathogens |volume=8 |issue=4 |pages=e1002619 |year=2012 |pmid=22577358 |pmc=3343118 |doi=10.1371/journal.ppat.1002619 |doi-access=free }}

Dying cells and foreign organisms are consumed by cells other than the "professional" phagocytes.{{cite journal

|vauthors=Birge RB, Ucker DS

| title = Innate apoptotic immunity: the calming touch of death | journal = Cell Death Differ. | volume = 15 | issue = 7 | pages = 1096–1102 |date=July 2008 | pmid = 18451871 | doi = 10.1038/cdd.2008.58 | doi-access = free }} These cells include epithelial cells, endothelial cells, fibroblasts, melanocyte and mesenchymal cells. They are called non-professional phagocytes, to emphasize that, in contrast to professional phagocytes, phagocytosis is not their principal function.{{cite journal

|vauthors=Couzinet S, Cejas E, Schittny J, Deplazes P, Weber R, Zimmerli S

| title = Phagocytic uptake of Encephalitozoon cuniculi by nonprofessional phagocytes| journal = Infect. Immun.| volume = 68 | issue = 12 | pages = 6939–45 |date=December 2000 | pmid = 11083817 | pmc = 97802 | doi = 10.1128/IAI.68.12.6939-6945.2000}} Fibroblasts, for example, which can phagocytose collagen in the process of remolding scars, will also make some attempt to ingest foreign particles.{{cite journal | pmid = 11112696 | volume=114 | issue=Pt 1 |date=January 2001 | pages=119–129 |vauthors=Segal G, Lee W, Arora PD, McKee M, Downey G, McCulloch CA | title = Involvement of actin filaments and integrins in the binding step in collagen phagocytosis by human fibroblasts | journal = Journal of Cell Science | doi=10.1242/jcs.114.1.119 }}

Non-professional phagocytes are more limited than professional phagocytes in the type of particles they can take up. This is due to their lack of efficient phagocytic receptors, in particular opsonins—which are antibodies and complement attached to invaders by the immune system. Additionally, most non-professional phagocytes do not produce reactive oxygen-containing molecules in response to phagocytosis.{{cite journal |vauthors=Rabinovitch M |title=Professional and non-professional phagocytes: an introduction |journal=Trends Cell Biol. |volume=5 |issue=3 |pages=85–87 |date=March 1995 |pmid=14732160 |doi= 10.1016/S0962-8924(00)88955-2}}

File:Staphylococcus aureus, 50,000x, USDA, ARS, EMU.jpg

A pathogen is only successful in infecting an organism if it can get past its defenses. Pathogenic bacteria and protozoa have developed a variety of methods to resist attacks by phagocytes, and many actually survive and replicate within phagocytic cells.{{cite web|url=http://textbookofbacteriology.net/antiphago.html|title=Mechanisms of Bacterial Pathogenicity: Bacterial Defense Against Phagocytes|last=Todar|first=Kenneth|publisher=2008|access-date=December 19, 2014}}{{cite journal |vauthors=Alexander J, Satoskar AR, Russell DG |title=Leishmania species: models of intracellular parasitism |journal=J. Cell Sci. |volume=112 |issue= 18|pages=2993–3002 |date=September 1999 |pmid=10462516 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=10462516 |doi=10.1242/jcs.112.18.2993 |access-date=December 19, 2014 }}

There are several ways bacteria avoid contact with phagocytes. First, they can grow in sites that phagocytes are not capable of traveling to (e.g., the surface of unbroken skin). Second, bacteria can suppress the inflammatory response; without this response to infection phagocytes cannot respond adequately. Third, some species of bacteria can inhibit the ability of phagocytes to travel to the site of infection by interfering with chemotaxis. Fourth, some bacteria can avoid contact with phagocytes by tricking the immune system into "thinking" that the bacteria are "self". Treponema pallidum—the bacterium that causes syphilis—hides from phagocytes by coating its surface with fibronectin,{{cite journal|vauthors=Celli J, Finlay BB| title = Bacterial avoidance of phagocytosis| journal = Trends Microbiol.| volume = 10| issue = 5| pages = 232–37|date=May 2002| pmid = 11973157| doi = 10.1016/S0966-842X(02)02343-0}} which is produced naturally by the body and plays a crucial role in wound healing.{{cite journal |vauthors=Valenick LV, Hsia HC, Schwarzbauer JE | title = Fibronectin fragmentation promotes alpha4beta1 integrin-mediated contraction of a fibrin-fibronectin provisional matrix | journal = Experimental Cell Research | volume = 309 | issue = 1 | pages = 48–55 |date=September 2005 | pmid = 15992798 | doi = 10.1016/j.yexcr.2005.05.024}}

Bacteria often produce capsules made of proteins or sugars that coat their cells and interfere with phagocytosis. Some examples are the K5 capsule and O75 O antigen found on the surface of Escherichia coli,{{cite journal |vauthors=Burns SM, Hull SI | title = Loss of resistance to ingestion and phagocytic killing by O(-) and K(-) mutants of a uropathogenic Escherichia coli O75:K5 strain | journal = Infect. Immun. | volume = 67 | issue = 8 | pages = 3757–62 |date=August 1999 | pmid = 10417134 | pmc = 96650 | doi = 10.1128/IAI.67.8.3757-3762.1999}} and the exopolysaccharide capsules of Staphylococcus epidermidis.{{cite journal |vauthors=Vuong C, Kocianova S, Voyich JM | title = A crucial role for exopolysaccharide modification in bacterial biofilm formation, immune evasion, and virulence | journal = J. Biol. Chem. | volume = 279 | issue = 52 | pages = 54881–86 |date=December 2004 | pmid = 15501828 | doi = 10.1074/jbc.M411374200 | doi-access = free }} Streptococcus pneumoniae produces several types of capsule that provide different levels of protection,{{cite journal |vauthors=Melin M, Jarva H, Siira L, Meri S, Käyhty H, Väkeväinen M | title = Streptococcus pneumoniae capsular serotype 19F is more resistant to C3 deposition and less sensitive to opsonophagocytosis than serotype 6B | journal = Infect. Immun. | volume = 77 | issue = 2 | pages = 676–84 |date=February 2009 | pmid = 19047408 | doi = 10.1128/IAI.01186-08 | pmc = 2632042}} and group A streptococci produce proteins such as M protein and fimbrial proteins to block engulfment. Some proteins hinder opsonin-related ingestion; Staphylococcus aureus produces Protein A to block antibody receptors, which decreases the effectiveness of opsonins.{{cite journal|vauthors=Foster TJ| title = Immune evasion by staphylococci| journal = Nat. Rev. Microbiol.| volume = 3| issue = 12| pages = 948–58|date=December 2005| pmid = 16322743| doi = 10.1038/nrmicro1289| s2cid = 205496221}} Enteropathogenic species of the genus Yersinia bind with the use of the virulence factor YopH to receptors of phagocytes from which they influence the cells capability to exert phagocytosis.{{cite journal |vauthors=Fällman M, Deleuil F, McGee K |title=Resistance to phagocytosis by Yersinia |journal=International Journal of Medical Microbiology |volume=291 |issue=6–7 |pages=501–9 |date=February 2002 |pmid=11890550 |doi= 10.1078/1438-4221-00159}}

File:Rickettsia rickettsii.jpg are small bacteria—here stained red—that grow in the cytoplasm of non-professional phagocytes.|alt=Two round cells with many tiny rod-shaped bacteria inside.]]

Bacteria have developed ways to survive inside phagocytes, where they continue to evade the immune system.{{cite journal

|vauthors=Sansonetti P

| title = Phagocytosis of bacterial pathogens: implications in the host response

| journal = Semin. Immunol. | volume = 13 | issue = 6 | pages = 381–90 |date=December 2001 | pmid = 11708894 | doi = 10.1006/smim.2001.0335

}} To get safely inside the phagocyte they express proteins called invasins. When inside the cell they remain in the cytoplasm and avoid toxic chemicals contained in the phagolysosomes.{{cite journal

|vauthors=Dersch P, Isberg RR| title = A region of the Yersinia pseudotuberculosis invasin protein enhances integrin-mediated uptake into mammalian cells and promotes self-association| journal = EMBO J.| volume = 18| issue = 5| pages = 1199–1213|date=March 1999| pmid = 10064587| pmc = 1171211| doi = 10.1093/emboj/18.5.1199}} Some bacteria prevent the fusion of a phagosome and lysosome, to form the phagolysosome. Other pathogens, such as Leishmania, create a highly modified vacuole inside the phagocyte, which helps them persist and replicate.{{cite journal |vauthors=Antoine JC, Prina E, Lang T, Courret N |title=The biogenesis and properties of the parasitophorous vacuoles that harbour Leishmania in murine macrophages |journal=Trends Microbiol. |volume=6 |issue=10 |pages=392–401 |date=October 1998 |pmid=9807783 |doi=10.1016/S0966-842X(98)01324-9}} Some bacteria are capable of living inside of the phagolysosome. Staphylococcus aureus, for example, produces the enzymes catalase and superoxide dismutase, which break down chemicals—such as hydrogen peroxide—produced by phagocytes to kill bacteria.{{cite journal |vauthors=Das D, Saha SS, Bishayi B | title = Intracellular survival of Staphylococcus aureus: correlating production of catalase and superoxide dismutase with levels of inflammatory cytokines | journal = Inflamm. Res. | volume = 57 | issue = 7 | pages = 340–49 |date=July 2008 | pmid = 18607538 | doi = 10.1007/s00011-007-7206-z | s2cid = 22127111 }} Bacteria may escape from the phagosome before the formation of the phagolysosome: Listeria monocytogenes can make a hole in the phagosome wall using enzymes called listeriolysin O and phospholipase C.{{cite journal|vauthors=Hara H, Kawamura I, Nomura T, Tominaga T, Tsuchiya K, Mitsuyama M| title = Cytolysin-dependent escape of the bacterium from the phagosome is required but not sufficient for induction of the Th1 immune response against Listeria monocytogenes infection: distinct role of Listeriolysin O determined by cytolysin gene replacement| journal = Infect. Immun.| volume = 75| issue = 8| pages = 3791–3801|date=August 2007| pmid = 17517863| pmc = 1951982| doi = 10.1128/IAI.01779-06}} M. tuberculosis infects neutrophils that are in turn ingested by macrophages and thereby infect latter as well.{{cite journal |vauthors=Parker HA, Forrester L, Kaldor CD, Dickerhof N, Hampton MB |title=Antimicrobial Activity of Neutrophils Against Mycobacteria |journal=Frontiers in Immunology |volume=12 |issue= |pages=782495 |date=2021 |pmid=35003097 |pmc=8732375 |doi=10.3389/fimmu.2021.782495 |doi-access=free |url=}} M. leprae infects macrophages, schwann cells, and neutrophils.

Bacteria have developed several ways of killing phagocytes. These include cytolysins, which form pores in the phagocyte's cell membranes, streptolysins and leukocidins, which cause neutrophils' granules to rupture and release toxic substances,{{cite journal|vauthors=Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N, Kansal RG, Kotb M, Nizet V| title = Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection| journal = Mol. Microbiol.| volume = 56| issue = 3| pages = 681–95|date=May 2005| pmid = 15819624| doi = 10.1111/j.1365-2958.2005.04583.x | s2cid = 14748436| doi-access = }}{{cite journal|vauthors=Iwatsuki K, Yamasaki O, Morizane S, Oono T|title=Staphylococcal cutaneous infections: invasion, evasion and aggression|journal=J. Dermatol. Sci.|volume=42|issue=3|pages=203–14|date=June 2006|pmid=16679003|doi=10.1016/j.jdermsci.2006.03.011}} and exotoxins that reduce the supply of a phagocyte's ATP, needed for phagocytosis. After a bacterium is ingested, it may kill the phagocyte by releasing toxins that travel through the phagosome or phagolysosome membrane to target other parts of the cell.

File:Leish amast WBC1 DPDx.JPG

Some survival strategies often involve disrupting cytokines and other methods of cell signaling to prevent the phagocyte's responding to invasion.{{cite journal |vauthors=Denkers EY, Butcher BA | title = Sabotage and exploitation in macrophages parasitized by intracellular protozoans | journal = Trends Parasitol. | volume = 21 | issue = 1 | pages = 35–41 |date=January 2005 | pmid = 15639739 | doi = 10.1016/j.pt.2004.10.004}} The protozoan parasites Toxoplasma gondii, Trypanosoma cruzi, and Leishmania infect macrophages, and each has a unique way of taming them. Some species of Leishmania alter the infected macrophage's signalling, repress the production of cytokines and microbicidal molecules—nitric oxide and reactive oxygen species—and compromise antigen presentation.{{cite journal|vauthors=Gregory DJ, Olivier M| title = Subversion of host cell signalling by the protozoan parasite Leishmania| journal = Parasitology| volume = 130 Suppl| pages = S27–35| year = 2005| pmid = 16281989| doi = 10.1017/S0031182005008139

| s2cid = 24696519}}

Macrophages and neutrophils, in particular, play a central role in the inflammatory process by releasing proteins and small-molecule inflammatory mediators that control infection but can damage host tissue. In general, phagocytes aim to destroy pathogens by engulfing them and subjecting them to a battery of toxic chemicals inside a phagolysosome. If a phagocyte fails to engulf its target, these toxic agents can be released into the environment (an action referred to as "frustrated phagocytosis"). As these agents are also toxic to host cells, they can cause extensive damage to healthy cells and tissues.Paoletti pp. 426–30

When neutrophils release their granule contents in the kidney, the contents of the granule (reactive oxygen compounds and proteases) degrade the extracellular matrix of host cells and can cause damage to glomerular cells, affecting their ability to filter blood and causing changes in shape. In addition, phospholipase products (e.g., leukotrienes) intensify the damage. This release of substances promotes chemotaxis of more neutrophils to the site of infection, and glomerular cells can be damaged further by the adhesion molecules during the migration of neutrophils. The injury done to the glomerular cells can cause kidney failure.{{cite journal|vauthors=Heinzelmann M, Mercer-Jones MA, Passmore JC| title = Neutrophils and renal failure | journal = Am. J. Kidney Dis. | volume = 34 | issue = 2 | pages = 384–99 |date=August 1999 | pmid = 10430993| doi = 10.1016/S0272-6386(99)70375-6}}

Neutrophils also play a key role in the development of most forms of acute lung injury.{{cite journal|vauthors=Lee WL, Downey GP| title = Neutrophil activation and acute lung injury| journal = Curr Opin Crit Care | volume = 7 | issue = 1 | pages = 1–7 |date=February 2001 | pmid = 11373504 | doi = 10.1097/00075198-200102000-00001 | s2cid = 24164360}} Here, activated neutrophils release the contents of their toxic granules into the lung environment.{{cite journal |vauthors=Moraes TJ, Zurawska JH, Downey GP | title = Neutrophil granule contents in the pathogenesis of lung injury | journal = Curr. Opin. Hematol. | volume = 13 | issue = 1 | pages = 21–27 |date=January 2006 | pmid = 16319683 | doi = 10.1097/01.moh.0000190113.31027.d5 | s2cid = 29374195 }} Experiments have shown that a reduction in the number of neutrophils lessens the effects of acute lung injury,{{cite journal|vauthors=Abraham E| title = Neutrophils and acute lung injury| journal = Crit. Care Med. | volume = 31 | issue = 4 Suppl | pages = S195–99 |date=April 2003 | pmid = 12682440 | doi =10.1097/01.CCM.0000057843.47705.E8| s2cid = 4004607}} but treatment by inhibiting neutrophils is not clinically realistic, as it would leave the host vulnerable to infection. In the liver, damage by neutrophils can contribute to dysfunction and injury in response to the release of endotoxins produced by bacteria, sepsis, trauma, alcoholic hepatitis, ischemia, and hypovolemic shock resulting from acute hemorrhage.{{cite journal |vauthors=Ricevuti G |title=Host tissue damage by phagocytes |journal=Ann. N. Y. Acad. Sci. |volume=832 |issue= 1|pages=426–48 |date=December 1997 |pmid=9704069 |doi= 10.1111/j.1749-6632.1997.tb46269.x|bibcode=1997NYASA.832..426R |s2cid=10318084 }}

Chemicals released by macrophages can also damage host tissue. TNF-α is an important chemical that is released by macrophages that causes the blood in small vessels to clot to prevent an infection from spreading.{{cite journal |vauthors=Charley B, Riffault S, Van Reeth K | title = Porcine innate and adaptative immune responses to influenza and coronavirus infections | journal = Ann. N. Y. Acad. Sci. | volume = 1081 | issue = 1| pages = 130–36 |date=October 2006 | pmid = 17135502 | doi = 10.1196/annals.1373.014 | pmc = 7168046 | bibcode = 2006NYASA1081..130C | hdl = 1854/LU-369324 | url = https://biblio.ugent.be/publication/369324 | doi-access = free }} If a bacterial infection spreads to the blood, TNF-α is released into vital organs, which can cause vasodilation and a decrease in plasma volume; these in turn can be followed by septic shock. During septic shock, TNF-α release causes a blockage of the small vessels that supply blood to the vital organs, and the organs may fail. Septic shock can lead to death.

File:Streptococcus Pyogenes (Group A Strep) (52606801786).jpg image of Streptococcus pyogenes (orange) during phagocytosis with a human neutrophil (blue)]]

Phagocytosis is common and probably appeared early in evolution,{{Harvnb|Sompayrac|2019|p=2}} evolving first in unicellular eukaryotes. Amoebae are unicellular protists that separated from the tree leading to metazoa shortly after the divergence of plants, and they share many specific functions with mammalian phagocytic cells.{{cite journal |vauthors=Cosson P, Soldati T | title = Eat, kill or die: when amoeba meets bacteria | journal = Curr. Opin. Microbiol. | volume = 11 | issue = 3 | pages = 271–76 |date=June 2008 | pmid = 18550419 | doi = 10.1016/j.mib.2008.05.005}} Dictyostelium discoideum, for example, is an amoeba that lives in the soil and feeds on bacteria. Like animal phagocytes, it engulfs bacteria by phagocytosis mainly through Toll-like receptors, and it has other biological functions in common with macrophages.{{cite book |vauthors=Bozzaro S, Bucci C, Steinert M |chapter=Phagocytosis and host-pathogen interactions in Dictyostelium with a look at macrophages |title=International Review of Cell and Molecular Biology | volume = 271 | pages = 253–300 | year = 2008 | pmid = 19081545 | doi = 10.1016/S1937-6448(08)01206-9 | isbn = 978-0-12-374728-0| s2cid = 7326149 }} Dictyostelium discoideum is social; it aggregates when starved to form a migrating pseudoplasmodium or slug. This multicellular organism eventually will produce a fruiting body with spores that are resistant to environmental dangers. Before the formation of fruiting bodies, the cells will migrate as a slug-like organism for several days. During this time, exposure to toxins or bacterial pathogens has the potential to compromise survival of the species by limiting spore production. Some of the amoebae engulf bacteria and absorb toxins while circulating within the slug, and these amoebae eventually die. They are genetically identical to the other amoebae in the slug; their self-sacrifice to protect the other amoebae from bacteria is similar to the self-sacrifice of phagocytes seen in the immune system of higher vertebrates. This ancient immune function in social amoebae suggests an evolutionarily conserved cellular foraging mechanism that might have been adapted to defense functions well before the diversification of amoebae into higher forms.{{cite journal

|vauthors=Chen G, Zhuchenko O, Kuspa A

| title = Immune-like phagocyte activity in the social amoeba | journal = Science | volume = 317 | issue = 5838 | pages = 678–81 |date=August 2007 | pmid = 17673666 | doi = 10.1126/science.1143991

| pmc = 3291017 | bibcode = 2007Sci...317..678C }} Phagocytes occur throughout the animal kingdom, from marine sponges to insects and lower and higher vertebrates.{{Harvnb|Delves|Martin|Burton|Roit|2006|pp=251–252}}{{cite journal |vauthors=Hanington PC, Tam J, Katzenback BA, Hitchen SJ, Barreda DR, Belosevic M | title = Development of macrophages of cyprinid fish | journal = Dev. Comp. Immunol. | volume = 33 | issue = 4 | pages = 411–29 |date=April 2009 | pmid = 19063916 | doi = 10.1016/j.dci.2008.11.004}} The ability of amoebae to distinguish between self and non-self is a pivotal one, and is the root of the immune system of many species of amoeba.

{{Reflist|30em}}

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• {{Cite book |last1=Delves |first1=P. J. |last2=Martin |first2=S. J. |last3=Burton |first3=D. R. |last4=Roit |first4=I. M. |title=Roitt's Essential Immunology |edition=11th |year=2006 |publisher=Blackwell Publishing |location=Malden, MA |isbn=978-1-4051-3603-7 }}
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• {{MeshName|Phagocytes}}
• [https://www.youtube.com/watch?v=JnlULOjUhSQ White blood cell engulfing bacteria]

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Category:Immune system

Category:Leukocytes